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• • C—CHEMISTRY; METALLURGY
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  • C12P7/00—Preparation of oxygen-containing organic compounds
  • C12P7/62—Carboxylic acid esters
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  • C12P7/00—Preparation of oxygen-containing organic compounds
  • C12P7/40—Preparation of oxygen-containing organic compounds containing a carboxyl group including Peroxycarboxylic acids
  • C12P7/42—Hydroxy-carboxylic acids
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
  • C12P11/00—Preparation of sulfur-containing organic compounds
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  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
  • C12P13/00—Preparation of nitrogen-containing organic compounds
  • C12P13/02—Amides, e.g. chloramphenicol or polyamides; Imides or polyimides; Urethanes, i.e. compounds comprising N-C=O structural element or polyurethanes
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
  • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
  • C12P17/10—Nitrogen as only ring hetero atom
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
  • C12P7/00—Preparation of oxygen-containing organic compounds
  • C12P7/02—Preparation of oxygen-containing organic compounds containing a hydroxy group
  • C12P7/22—Preparation of oxygen-containing organic compounds containing a hydroxy group aromatic
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
  • C12P7/00—Preparation of oxygen-containing organic compounds
  • C12P7/64—Fats; Fatty oils; Ester-type waxes; Higher fatty acids, i.e. having at least seven carbon atoms in an unbroken chain bound to a carboxyl group; Oxidised oils or fats
  • C12P7/6436—Fatty acid esters

Definitions

• the invention pertains to an improved process for the preparation of phenolic carboxylic acid derivatives catalysed by enzymatic esterification or amidation of the corresponding free acid or the lower alkyl ester.
• So-called sterically hindered 3-hydroxyphenylpropionic acid esters and certain amide derivatives are well known as effective antioxidants for a wide variety of organic substrates, particularly lubricants and polymers, protecting them from oxidative and thermal degradation. Many of these esters have gained wide commercial acceptance as phenolic antioxidants. So-called sterically hindered 3-hydroxyphenylpropionic acid esters substituted at the phenyl ring by tert-butyl and a benzotriazolyl group are known as efficient UV-absorber molecules.
• R is a lower alkyl radical and R 1 is an ester group of higher chain length.
• the reaction is an equilibrium reaction. In general, the lower-boiling alcohol liberated is distilled off during the reaction.
• Various catalysts for this reaction are known (Junzo Otera, Chem. Rev., 93 (1993) 1449-1470), e.g. acids, bases, amines, metal alkoxides and also, inter alia, organotin compounds. Many of these esterification reactions are carried out at higher temperatures in the range from 80° C. to above 200° C.
• Suitable heterogeneous transesterification catalysts include lithium amide, aluminium isopropylate and dibutyltin oxide.
• U.S. Pat. No. 4,594,444 discloses a process for the preparation of sterically hindered 3-hydroxyphenylpropionic acid esters by the transesterification in the presence of an oxide or an organometallic compound of a metal of the fourth main group or transition metal group of the Periodic Table as catalyst in an amount between 0.05 and 1.0 mol percent based on the methyl or ethyl ester.
• Higher dialkyltin oxides, particularly dibutyltin oxides are taught as the preferred catalyst for this process.
• L is an at least divalent radical and at least one of the free valences of the Si in the above partial formula is bound to the inorganic support.
• the present invention relates to a process for the preparation of a compound of the formula:
• the enzymatically catalysed esterification, transesterification or amidation process according to the present invention operates under mild conditions, such as low temperatures and under neutral or nearly neutral pH conditions.
• the biocatalysts used can be separated from the reaction product simply and completely by known solid/liquid separation operations, for example filtration, centrifugation or decantation.
• the biocatalysts that have been filtered off remain catalytically active and may be reused a number of times, particularly in continuous processes.
• the compounds (I) obtainable by the process according to the present invention are, for example, valuable antioxidants against oxidative, thermal or actinic degradation of organic compositions of matter.
• Such compositions are, for example, natural or synthetic polymers, functional liquids, such as lubricants, hydraulic fluids or metalworking fluids, etc.
• Some compounds (I) substituted at the phenyl ring by a tert-butyl and a benzotriazolyl group are known as efficient UV-absorber molecules.
• the various alkyl groups defined above of different chain length comprise saturated linear or, where possible, branched hydrocarbon groups, particularly C 1 -C 9 alkyl, e.g. methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, 2-ethylbutyl, 1-methylpentyl, 1,3-dimethylbutyl, n-heptyl, 3-heptyl, 1-methylhexyl, isoheptyl, n-octyl, 2-ethylhexyl, 1,1,3,3-tetramethylbutyl, 1-methylheptyl, n-nonyl or 1,1,3-trimethyihexyl, as well as C 10 -C 45 salkyl, particularly straight chained C 10 -C 45 alkyl, e
• (C 1 -C 4 Alkyl) 1-3 phenyl is, for example, 2- or 4-tolyl, 2,5- or 2,6-xylyl, mesityl, 2- or 4-ethylphenyl, 2,4- or 2,6-diethylphenyl, 4-cumenyl, 2-tert-butyl-6-methylphenyl or 2,6-bis-tert-butyl.
• Phenyl-C 1 -C 3 alkyl is, for example, phenyl attached to C 1 -C 3 alkyl in 1-, 2- or 3-position, e.g. 2-phenylethyl, particularly benzyl.
• (C 1 -C 4 Alkyl) 1-3 phenyl-C 1 -C 3 alkyl is one of the above mentioned (C 1 -C 4 alkyl) 1-3 phenyl attached to C 1 -C 3 alkyl in 1-, 2- or 3-position, e.g. 2-tert-butyl-6-methylbenzyi or 2,6-bis-tert-butyl-phenyl.
• Cycloalkyl is, for example, cyclopentyl or cyclohexyl.
• C 1 -C 4 Alkyl 1-3 C 5 -C 12 cycloalkyl is one of the above-mentioned C 5 -C 12 cycloalkyl groups substituted with 1-3 C 1 -C 4 alkyl, e.g. 2- or 4-methylcyclohexyl, 2,6-dimethylcyclohexyl, 2,4,6-trimethylcyclohexyl or 4-tert-butylcyclohexyl.
• Alkenyl of different chain length is, for example, vinyl, allyl, 2-butenyl, methallyl, 2- or 3-hexenyl, or 3- or 5-decenyl.
• the partial formula (A) comprises within its scope the following isomer:
• R 1 and R 2 represents methyl or tert-butyl and the other one represents tert-butyl
• Y represents straight chained or branched C 10 -C 22 alkyl and Y 2 represents 2-hydroxyethyl.
• Another preferred alternative embodiment relates to the preparation of compounds (I), wherein n represents 3, m represents zero and Y represents the trivalent group:
• Another preferred alternative embodiment relates to the preparation of compounds (I), wherein n represents 4 and m represents zero.
• a preferred embodiment of the invention relates to a process for the preparation of a compound (I), wherein
• a particularly preferred embodiment of the invention relates to a process for the preparation of a compound (I), wherein
• a highly preferred embodiment of the invention relates to a process for the preparation of a compound (I), wherein
• Another highly preferred embodiment of the invention relates to a process for the preparation of a compound (I), wherein
• a most preferred embodiment of the invention relates to a process for the preparation of a compound (I), wherein
• the process steps of the preferred embodiments are described below.
• the inventive process comprises the following steps:
• a suitable reactive leaving group —X is, for example the hydroxy or C 1 -C 4 alkoxy group, particularly methoxy.
• Enzymatic catalysis according to the process of the present invention is performed in the presence of a suitable biocatalyst, such as enzymes, e.g. hydrolases, especially esterases, amidases, lipases and proteases, such as the ones described in Hydrolases in Organic Synthesis; Wiley-VCH (U. T. Bornscheuer, R. T. Kazlauskas) 1999, pages 65-195, ISBN 3-527-30104-6.
• a suitable biocatalyst such as enzymes, e.g. hydrolases, especially esterases, amidases, lipases and proteases, such as the ones described in Hydrolases in Organic Synthesis; Wiley-VCH (U. T. Bornscheuer, R. T. Kazlauskas) 1999, pages 65-195, ISBN 3-527-30104-6.
• esterases are those obtained from the intestines of warm-blooded animals, such as horse liver esterase, porcine liver esterase or porcine pancreas lipase (PPL), fungal esterases or esterases from microorganisms, such as Bacillus subtilis, Pichia polimorpha Rhizopus sp. or Penicillium sp. or yeast esterases.
• Suitable lipases include those of animal, plant and microbiological origin, particularly those found in many strains of bacteria and fungi, such as esterases from Candida, Alcaligene species or Pseudomonas species, such as Amano P or the lipase from Pseudomonas spec DSM 8246. Specific examples are Aspergillus niger (Amono AP6). G. candidum (GCL), H. lanuginosa (HLL). Rhizopus sp. (RML, ROL), Candida sp. (CCL), such as the ones from Candida antarctica (CAL-A, CAL-B), Aspergillus sp. (ANL), Pseudomonas sp.
• Suitable enzymes are proteolytic enzymes, too, such as subtilisin, thermitase, chymotrypsin, thermolysin, papain, aminoacylase, penicillin amidase or trypsin. Suitable enzymes are known to those skilled in the art and are not limited to the ones mentioned above.
• the enzymes can be employed as crude extracts, in pure form or in immobilised crude or pure form, particularly on a support or carrier, to which they are linked chemically or physically.
• Suitable supports are for example, silica gel, diatomite, Celite®, Eupergit® (Röhm & Haas, Darmstadt, Germany) and the like. Such methods are described by W. Tischer et al. TIBTECH 1999, 17, 326; J. Lalonde, Curr. Oin. Drug Disc. & Develop. 1998, 1(3) 271.
• the enzymes can also be employed as cross-linked-enzymes (CLEC's), which enzymes may be obtained from Altus Corp. Suitable enzymes are well known and are described, for example, in Hydrolases in Organic Synthesis ; Wiley-VCH, loc. cit. pages 61-64, Biotransformation in Organic Chemistry (K. Faber), Springer Verl. 1997, 3 rd Ed., pages 345-357, ISBN 3-540-61688-8; Biotechnology (H.-J. Rehm, G. Reed), VCH 1998, 2 nd Ed. Pages 407-411.
• CLEC's cross-linked-enzymes
• enzymes that are commercially available, such as the hydrolases available from Novo Nordisk (Enzyme Toolbox), particularly the lipases SP 523, 524, 525 and 526 and Novozyme®435 (recombinant Candida antarctica lipase B (E. M. Anderson et al. Biocat. Biotransf. 1998, 16 181)), NOVO Nordisk, Bagswaerd, Denmark) or the enzyme QLM, QL (Meito Sangyo, Japan) or enzymes that are well known and described, e. g. by H.-J. Rehm and G. Reed in Biotechnology, loc. cit., pages 40-42).
• immobilised lipases that are thermostable, such as Rhizomucor miehei immobilised lipase (Lipozyme®) or NOVOZYME 435.
• Enzymes having esterase, lipase and/or protease activity may be obtained from natural sources and/or from microorganism using standard procedures known in the art, for example from cloning processes via expression and amplification.
• An alternative embodiment relates to the inclusion of the enzymatic biocatalyst in a semi-permeable membrane. This increases the stability of the biocatalyst and its separability from reagents, reactants and products.
• Another advantage is the suitability of the process according to the invention for a continuous process in an appropriate reaction vessel.
• Such methods are described by V. M. Balcao et al. Enzyme Microbiol. Techn. 1996, 18 392; L. Giorno et al. TIBTECH 2000, X, 339.
• the instant enzymatic esterification, transesterification or amidation process is carried out at lower temperatures, especially from 10-80° C., preferably from 25- 60° C.
• the process can be carried out without adding a solvent.
• a solvent such as hexane, toluene, benzene, THF, diethyl ether, methyl-tert-butyl ether, methylene chloride and the like is optional.
• the amount-of the enzyme catalyst depends on the substrate used and on the reaction conditions, such as temperature, reaction time, solvent, but may be from 0.01 to 20.0% by weight, preferably from 1.0 to 10.0% by weight, based on the weight of the reactants.
• the reaction time for performing the process depends on the amount of reactants used and on the activity of the enzyme catalyst, and amounts to, for example, 48 hours, preferably 24 hours.
• the product HX formed in the process in particular water or the lower alkanol is removed by routine methods, for example by vacuum distillation.
• the reactive leaving group —X is replaced by enzymatic catalysis with a mono-, bi-, tri- or tetravalent group —Y. that corresponds to the value of the numeral n, in the presence of a suitable alcohol (esterification, transesterification) or a suitable amine (amidation).
• n 1, the esterification or transesterification is performed with the alcohol HO—Y, that corresponds to the monovalent groups —O—Y 1 .
• the amidation is performed with an amine HN(—Y 2 ) 2 that corresponds to the group or —N(—Y 2 ) 2 .
• n 2
• the transesterification is performed with the alcohol selected from the group consisting of HO—C x H 2x —OH (D′),
• amidation is performed with hydrazine, if z is zero, or with the diamine: —NH—(CH 2 ) z —NH— (H′),
• n 3
• the esterification or transesterification is performed with an alcohol corresponding to:
• esterification, transesterification or amidation processes generally require a time period from 1 to 10 hours, advantageously from 1 to 5 hours and preferably from 1 to 3 hours, to achieve optimum yields.
• the biocatalyst can, for example, be present in the reaction mixture as a suspension of a powder.
• Use of the catalyst in a fixed bed is a preferred option of carrying out the process.
• the present invention also relates to the reaction mixture, which consists of a composition comprising
• compositions optionally present in the composition are the above-mentioned compounds (II), e.g. as unreacted reactants, and the above-mentioned solvents.
• the enzyme catalyst After finishing the biocatalysed reaction, the enzyme catalyst can be separated off by known methods, such as filtration or decantation, and used a number of times.
• the products (I) obtained by the process according to the invention and the reactants (II) are known or can be obtained by methods known per se.
• the products prepared by the process according to the invention are, for example, useful antioxidants against oxidative, thermal or actinic degradation of degradable organic substrates.
• Suitable substrates are, for example, synthetic or natural polymers or functional fluids, such as lubricants, hydraulic fluids or metalworking fluids, etc.
• the reaction product is obtained by purification with silica gel (hexane/ ethyl acetate 10:4) and removal of the solvent.
• a melt of 5 equivalents 3-(3,5-di-tert-butyl4-hydroxyphenyl)-propionic acid methyl ester and 1 equivalent bis-(2-hydroxyethyl)sulphide is mixed with 5-10 wt. % NOVOZYME 435 are stirred at 200 mbar for 24 h at 70-80 ° C. After dissolving the reaction mixture in THF, filtering off the enzyme and distilling off the surplus of the ester component the product is obtained as the residue.
• Example 9 In a manner analogous to Example 9 the above compound is obtained from a melt of 1 equivalent 1,3,5-tris-(2-hydroxy-ethyl)-1,3,5-triazinane-2,4,6-trione und 10 equivalents 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-propionic acid methyl ester with 5-10 wt. % LIPOZYME RM IM and removal of the surplus ester component.
• Example 9 In a manner analogous to Example 9 the above compound is obtained from a melt of 1 equivalent hydrazine hydrate solution (24-26%) und 7-10 equivalents 3-(3,5-di-tert-butyl-4-hydroxy-phenyl)-propionic acid methyl ester with 5-10 wt % LIPOZYME RM IM and removal of the surplus ester component.
• the product is purified by crystallisation from xylene.
• Example 9 In a manner analogous to Example 9 the above compound is obtained from a melt of 10 equivalents 3-(3,5-di-tert-butyl4-hydroxyphenyl)-propionic acid vinyl ester and 1 equivalent pentaerythritol with 5-10 wt. % LIPOZYME TL IM and removal of the surplus ester component.
• 3-(3-Benzotriazole-2-yl-5-tert-butyl-4-hydroxyphenyl)-propionic acid methyl ester is dissolved in 10 equivalents 1-n-octanol and stirred at 60° C. and 500 mbar with 5 wt. % LIPOZYME RM IM or LIPOZYME TL IM 2-5 d. After removal of the solvent and the surplus ester component the pure product is obtained.
• 3-(3-Benzotriazole-2-yl-5-tert-butyl-4-hydroxyphenyl)-propionic acid methyl ester is dissolved in 10 equivalents 2-ethyl-1-hexanol and stirred at 60° C. and 500 mbar with 5 wt. % LIPOZYME RM IM or LIPOZYME TL IM 2-5 d. After removal of the solvent and the surplus ester component the pure product is obtained.

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